CN104622815A - Cyclic ether side group-containing amphiphilic polymer lyophilized powder and composition thereof, and applications of composition - Google Patents
Cyclic ether side group-containing amphiphilic polymer lyophilized powder and composition thereof, and applications of composition Download PDFInfo
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Abstract
The present invention relates to cyclic ether side group-containing amphiphilic polymer lyophilized powder and a composition thereof, and applications of the composition, wherein the lyophilized powder is the lyophilized powder of a cyclic ether side group-containing amphiphilic polymer or the drug-loaded lyophilized powder adopting a cyclic ether side group-containing amphiphilic polymer as an auxiliary material, the amphiphilic polymer is selected from one or a plurality of ABA type and BAB type amphiphilic block copolymers comprising a degradable polyester A containing a 1,4,8-trioxaspiro[4.6]-9-undecanone (TOSUO) unit and a polyethylene glycol block B, and the polyester A is a copolymer of caprolactone, lactide, glycolide and TOSUO. According to the present invention, the lyophilized powder can be rapidly dispersed into an aqueous medium at a temperature of 4-25 DEG C to form a flowable liquid and can be rapidly gelated under the body temperature environment; and the pyrogen-free powder injection after the sterilization treatment can be used for the clinical topical drug administration application, is sued for the topical drug administration on the intratumoral position, the peritumoral position, the thoracic cavity, the peritoneal cavity, the Intravesical position, the position in the liver, the intranasal position, the intraocular position, the intravaginal position and other positions, and the drug can be subjected to long-acting slow-release.
Description
Technical field
Take degradable polymer as the medicament slow release dosage form of adjuvant and technology of preparing thereof and application, for the long-acting slow-release of topical.
Background technology
Injectable amphipathic nature polyalcohol temperature sensing in situ gel rubber is that the long-acting slow-release of topical provides new tool.There is the polymer temperature-sensitive hydrogel of sol-gel transition character, flowable liquid under room temperature, be expelled in body and then form gel (without the need to chemical reaction and organic solvent) in injection site original position, can the local release of medicine in long-acting control gel, and to injection site, there is Morphological adaptability, very suitable tumor-localizing administration.Polymer temperature sensing in situ gel rubber for topical mainly comprises the aqueous dispersions of the amphipathic nature polyalcohol that the natural polymers such as chitosan, improvement on synthesis (ELPs) and PEG modify, as poloxamer (oxirane and propylene oxide block copolymer), PLGA-PEG-PLGA (trade name
), the amphipathic degradable polymer such as PEG and polycaprolactone (PCL), poly phosphazene.Current temperature sensing in situ gel rubber system has following shortcoming: 1. hydrophobic drug and aqueous solutions of polymers need be disperseed more than 24 hours at 4 DEG C when using, and drug crystallization can affect the release of medicine; 2. greatly, injections difficult, is unsuitable for the conveying of hydrophobic therapeutic agent, and uncontrollable structure is that the control of gelling performance brings difficulty for natural polymer and improvement on synthesis solution viscosity; 3. poloxamer, body inner gel corrosion low to hydrophobic drug drug loading is too fast and can not degrade; 3.PLGA-PEG-PLGA is at room temperature thick, not easily shifts and weighs, and the colloidal sol of preparation needs freezer storage, must melt rear use; 4. the preparation of poly-phosphorus eyeball is loaded down with trivial details, is difficult to scale preparation.The problems referred to above significantly limit the development and application of Injectable temperature sensitive gel preparation.
Therefore, for convenience of storage and the transport of Injectable polymer thermosensitive hydrogel preparation, and apply convenience clinically, need to develop that a kind of have under stable storing, room temperature can rapid dispersion, PhastGel and be suitable for the lyophilized powder dosage form of the Injectable temperature sensitive gel of multi-medicament under body temperature.The Thermo-sensitive amphipathic nature polyalcohol (CN201010200249.9 and CN201110436994.8) of this seminar early development containing cyclic ether side base, on this basis, we form lyophilized powder dosage form to the above-mentioned polymer of employing and have carried out further technical research, define the lyophilized powder in the present invention and compositions technology thereof.
Summary of the invention
The object of the invention is to store and Injectable temperature sensitive gel preparation easy to use for clinical topical provides a kind of, that a kind of room temperature adopting the amphipathic nature polyalcohol of ad hoc structure to be formed is easy to redispersion and the lyophilized powder had good stability, facilitate doctor according to the needs of patient treatment, carry out the regulation and control of compatibility of drugs and dosage, through local simple injection or smear, medicine is fixed on agents area, long-acting slow-releasing medicine, to improve curative effect of medication, to reduce toxic and side effects, reduce times for spraying, improve the compliance of patient medication.
The present invention relates to a kind of lyophilized powder containing cyclic ether side base amphipathic nature polyalcohol, described lyophilized powder is a kind of lyophilized powder containing amphipathic nature polyalcohol, and wherein amphipathic nature polyalcohol mass content accounts for more than 65%, and freeze-dried excipient accounts for 0-10%, and medicine accounts for 0 ~ 30%; The feature of described lyophilized powder is: 20 DEG C, dispersible in normal saline within 120min formed amphipathic nature polyalcohol mass content 10% ~ 40% uniform aqueous dispersions, viscosity is less than 600Pa.s, place 6h viscosity B coefficent at 20 DEG C lower than 20%, the aqueous dispersions formed can gelation in 10min at 37 DEG C; Described amphipathic nature polyalcohol is by containing 1,4, one or more in ABA, BAB type amphipathic nature block polymer that the degradable polyester A of 8-trioxa spiral shell [4.6]-9-hendecanone (TOSUO) unit and Polyethylene Glycol B block form, wherein, polyester A is the copolymer of caprolactone, lactide, Acetic acid, hydroxy-, bimol. cyclic ester and TOSUO; TOSUO construction unit accounts for the 5-20% of A, and further preferably 7 ~ 15%; The average molecular mass of A is 1000 to 10000, and the average molecular mass of Polyethylene Glycol block is 500 to 5000; The total mass ratio of A and B is 2-4; Heavy metal <0.01% in polymer, solvent and level of residual monomers <0.5%; Described freeze-dried excipient is selected from mannitol, glucose, lactose, dextran, sucrose, gelatin hydrolysate, sodium chloride, citric acid, glycine, Glycine sodium, sodium deoxycholate, sodium dihydrogen phosphate and sodium hydrogen phosphate, sorbitol, dextran and their combination.
Described lyophilized powder can be the lyophilized powder of the amphipathic nature polyalcohol being loaded with medicine, wherein amphipathic nature polyalcohol content is more than 65%, freeze-dried excipient 0-10%, heavy metal <0.01%, water content <1%, solvent and level of residual monomers <0.5%, medicine is one or more in chemical medicine, Chinese medicine and biological species medicine, and content is 0.5 ~ 30%; Described amphipathic nature polyalcohol is by containing 1,4, one or more in ABA, BAB type amphipathic nature block polymer that the degradable polyester A of 8-trioxa spiral shell [4.6]-9-hendecanone (TOSUO) unit and Polyethylene Glycol B block form, wherein, polyester A is the copolymer of caprolactone, lactide, Acetic acid, hydroxy-, bimol. cyclic ester and TOSUO, TOSUO construction unit accounts for the 5-20% of A, and the average molecular mass of A is 1000 to 10000, and the average molecular mass of Polyethylene Glycol block is 500 to 5000; The total mass ratio of A and B is 2-4; Described freeze-dried excipient is selected from mannitol, glucose, lactose, dextran, sucrose, gelatin hydrolysate, sodium chloride, citric acid, glycine, Glycine sodium, sodium deoxycholate, sodium dihydrogen phosphate and sodium hydrogen phosphate, sorbitol, dextran and their combination; Described lyophilized powder dispersibles in normal saline and forms 25% aqueous dispersions within 20oC, 120min, and viscosity is less than 600Pa.s, and place 6h viscosity B coefficent at 20 DEG C lower than 20%, the aqueous dispersions formed is 10min inner gel at 37 DEG C.
Above-mentioned lyophilized powder 20 DEG C, dispersible in normal saline within 120min and form 25% aqueous dispersions, viscosity is less than 600Pa.s, and place 6h viscosity B coefficent at 20 DEG C lower than 20%, the aqueous dispersions formed is 10min inner gel at 37 DEG C.
Medicine in described lyophilized powder is antitumor drug, comprises one or more in antitumor chemical medicine, Chinese medicine and biological species medicine.
Described a kind of lyophilized powder containing cyclic ether side base amphipathic nature polyalcohol, feature is the medicine in described lyophilized powder is hydrophobic anticancer drug, and lyophilized powder drug content is 1-30%, preferred paclitaxel, amycin, hydroxy camptothecin.
Described prepares by the following method containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder, feature is: the preparation of (1) ABA type amphipathic nature polyalcohol and purification: take Polyethylene Glycol as initiator, stannous octoate is catalyst, 1,4,8-trioxa spiral shell [4.6]-9-hendecanone and caprolactone or lactide or Acetic acid, hydroxy-, bimol. cyclic ester or their mixture are that monomer carries out ring-opening polymerisation, specifically: Polyethylene Glycol is added reactor, heating makes Polyethylene Glycol melting, natural cooling after evacuation dewaters, add caprolactone or lactide or Acetic acid, hydroxy-, bimol. cyclic ester or their mixture, TOSUO and stannous octoate successively, stannous octoate consumption is less than 0.5% of reactant gross mass, often add evacuation, inflated with nitrogen after a kind of reactant, last vacuum seal, reacts 3-24 hour under stirring at 120-160 DEG C, in reactor, add the polymer synthesized by dichloromethane dissolving, then pour in cold normal hexane and precipitate, collected by filtration thing, in triplicate, sucking filtration isolates precipitate in this operation, and vacuum drying obtains ABA type amphipathic nature polyalcohol, the preparation of BAB type amphipathic nature polyalcohol and purification: take poly glycol monomethyl ether as initiator, stannous octoate is catalyst, 1,4,8-trioxa spiral shell [4.6]-9-hendecanone and caprolactone or lactide or Acetic acid, hydroxy-, bimol. cyclic ester or their mixture are that monomer carries out ring-opening polymerisation, its product is dissolved in dry toluene, with hexamethylene diisocyanate or paraphthaloyl chloride for coupling agent carries out coupling reaction, specifically: poly glycol monomethyl ether is added reactor, heating makes its melting, natural cooling after evacuation dewaters, add caprolactone or lactide or Acetic acid, hydroxy-, bimol. cyclic ester or their mixture, TOSUO and stannous octoate successively, after often adding a kind of reactant, in a heated condition, evacuation, inflated with nitrogen remove residual water, last vacuum seal, reacts 3-24 hour under stirring at 120-160 DEG C, the polymer synthesized by dichloromethane dissolving is added in reactor, then will pour in cold normal hexane and precipitate, collected by filtration thing, this operation in triplicate, sucking filtration isolates precipitate, product after vacuum drying is dissolved in dry toluene, and with hexamethylene diisocyanate or paraphthaloyl chloride for coupling agent, triethylamine is acid binding agent, in 60 or 80 DEG C, stirring reaction 8-24 hour, pours into reactant liquor in cold normal hexane and precipitates, collected by filtration thing, this operation in triplicate, sucking filtration isolates precipitate, vacuum drying, obtains the amphipathic copolymer of BAB type, (2) hydrophobic drug ABA or BAB type being contained cyclic ether side base amphipathic nature polyalcohol and required load is dissolved in volatile organic solvent, be configured to the polymer solution of 10-20%, after 0.22 micron pore membrane filtration sterilization, under gnotobasis, join the sterile distilled water with agitating device, or contain in the aqueous humour of excipient and (or) water soluble drug, polymer solution and hydatoid volume ratio are 1:3-10, stir after 3-6 hour, after solvent volatilization is clean, obtained aqueous polymer dispersion is dispensed in lyophilizing container, after freezing at-40 DEG C, lyophilization, sealed packaging, after obtained freeze-drying powder carries out further sterilizing by ultraviolet, then pack.
The described compositions containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder is also related in the present invention, be the flowable fluid composition that one or both and above lyophilized powder in described lyophilized powder form with the aqueous humour at least containing 75% water, wherein amphipathic nature polyalcohol content is at 15-40%; At 25 DEG C, composition viscosity, at 10-600Pas, is preferably placed 6 hours viscosity changes at 15 ~ 100Pas, 4-25 DEG C and is less than 20%, still keep syringeability, under 32-42 DEG C or body temperature environment, can form gel in 2-10 minute; Described aqueous humour refer to containing or not containing the injectable aqueous humour of therapeutic agent, therapeutic agent content lower than 25%, described therapeutic agent refer in chemotherapeutics, Chinese medicine and biological species medicine one or more; The total amount of the therapeutic agent in the medicine of load in lyophilized powder in lyophilized powder compositions and aqueous humour accounts for the 0.1-25% of compositions; The preparation method of lyophilized powder compositions is: at 4-25 DEG C, mixed by lyophilized powder with aqueous humour, through gentle agitation or vortex 0.5-2 hour, forms homogeneous flowable fluid composition.
Described a kind of compositions containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder, be by containing paclitaxel or (with) lyophilized powder of amycin and the aqueous solution of water-soluble anti-tumor medicine form injectable fluid composition, for antitumor drug associating topical; Described water-soluble anti-tumor medicine comprise in antineoplastic chemotherapy medicine, Chinese medicine and biological species medicine one or more.
The described compositions containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder, adopts the aqueous humour containing 0.1-5% adhesive agent to configure; Described adhesive agent is selected from hyaluronic acid, Chitosan-phospholipid complex, cyclodextrin, mucopolysaccharide, water-soluble cellulose derivative, acrylic polymer; The acid of preferably clear matter, carbomer, carbopol; Preferred average molecular mass is at the hyaluronic acid of 5-30 ten thousand further.
The application of the described compositions containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder, feature be as gel preparation in tumor, by tumor, thoracic cavity, abdominal cavity, intravesical, in liver, nasal cavity, ophthalmic, intravaginal topical.
The topical being applied to thoracic cavity, abdominal cavity, intravesical antitumor drug of described lyophilized powder compositions, method first discharges thoracic cavity, seroperitoneum or intravesical urine, then by prepare in advance fluid composition injection or be applied to medicine-feeding part.
Accompanying drawing explanation
Fig. 1. lyophilized powder FP-2, is dispersed into 25% aqueous dispersions in 25 DEG C of normal saline and has flowable, gelation at 37 DEG C.
Fig. 2 lyophilized powder FP-3, is dispersed into 25% aqueous dispersions in 25 DEG C of normal saline and has flowable, gelation at 37 DEG C.
Fig. 3 compositions A-1 at 25 DEG C can flow regime, 37 DEG C form gels.
Fig. 4 compositions A-13 at 25 DEG C can flow regime, 37 DEG C form gels.
In Fig. 5 embodiment 40, compositions A-8 is under dosage is 0.5mg/kg, after mice injection into liver, and body weight change.
Detailed description of the invention
Embodiment 1
The Polyethylene Glycol (1.50g) of relative molecular mass 1000 is added reactor, and heating makes Polyethylene Glycol melting, natural cooling after evacuation dewaters; Add caprolactone (2.79g), TOSUO(0.21g successively) and stannous octoate (14mg), often add evacuation, inflated with nitrogen after a kind of reactant, last vacuum seal, reacts 24 hours under stirring at 120 DEG C; In reactor, add the polymer synthesized by dichloromethane dissolving, then pour in cold normal hexane and precipitate, collected by filtration thing, in triplicate, sucking filtration isolates precipitate in this operation, vacuum drying, obtains ABA type amphipathic nature polyalcohol P-1.Content of beary metal is lower than 0.001%(quality), monomer and solvent residual amount are lower than 0.05%(quality).
Embodiment 2
By molecular weight be 700 poly glycol monomethyl ether (7.2g) add reactor, heating make its melting, natural cooling after evacuation dewaters; Add caprolactone (18.36g), TOSUO (3.24g) and stannous octoate (108mg) successively, often add evacuation, inflated with nitrogen after a kind of reactant, last vacuum seal, react 10 hours at 160 DEG C; Add the polymer synthesized by dichloromethane dissolving to reactor, then pour in cold normal hexane and precipitate, collected by filtration thing, in triplicate, sucking filtration isolates precipitate in this operation, vacuum drying, obtains the diblock copolymer containing cyclic ether side base; Above-mentioned product (22.4g) is dissolved in dry toluene (100ml), heating, evacuation, the water of removing Polymer absorption remains 50ml to toluene, then hexamethylene diisocyanate (432mg) is added, stirring reaction 8-24 hour under 60 DEG C of conditions, pours into reactant liquor in cold normal hexane and precipitates, collected by filtration thing, repeat 2 precipitation purification steps, sucking filtration isolates precipitate, vacuum drying, obtains the amphipathic copolymer p-7 of BAB type.Content of beary metal is lower than 0.001%(quality), monomer and solvent residual amount are lower than 0.05%(quality).
Embodiment 3:
Ratio between the relative molecular mass of Polyethylene Glycol and monomer, with embodiment 1 and embodiment 2, is just changed into the data in table 1 by device and operation, feeds intake, prepare other block copolymer in table 1 by the raw material composition shown in table 1.Need to carry out twice or more the precipitation purification of number of times, until heavy metal and compounds content (mainly stannous octoate) thereof are lower than 0.001% in polymer, monomer and solvent residual amount are lower than 0.05%.
Detect content of beary metal according to national FDA standards of pharmacopoeia method, monomer and organic solvent residual adopt gas chromatography determination.Amphipathic nature polyalcohol composition is in table 1
Table 1 is containing cyclic ether side based, biodegradable amphipathic nature block polymer composition
M
brepresent the relative molecular mass of Polyethylene Glycol block; M
arepresent the relative molecular mass of hydrophobic polyester block; m
trepresent the mass percentage that TOSUO unit accounts for polyester block; m
a: represent the mass percentage that hydrophobic polyester block accounts for block copolymer.CL represents caprolactone; LA represents lactide; GA represents Acetic acid, hydroxy-, bimol. cyclic ester
Embodiment 11
Will containing cyclic ether side base amphipathic nature polyalcohol P-1(0.8g) be dissolved in oxolane (5mL), after 0.22 micron pore membrane filtration sterilization, in an aseptic environment, join the sterile distilled water (15mL) with agitating device, stir after 3-6 hour, after solvent volatilization is clean, obtained aqueous polymer dispersion is dispensed in lyophilizing container, after freezing at-40 DEG C, lyophilization, sealed packaging; After obtained freeze-drying powder FP-1-1 carries out further sterilizing by oxirane, then pack.
Embodiment 12
Will containing cyclic ether side base amphipathic nature polyalcohol P-1(0.9g) be dissolved in oxolane (5mL), after 0.22 micron pore membrane filtration sterilization, in an aseptic environment, the mannitol concentration joined with agitating device is 0.5%(20mL), stir after 3-6 hour, after solvent volatilization is clean, obtained aqueous polymer dispersion is dispensed in lyophilizing container, after freezing at-40 DEG C, lyophilization, sealed packaging; After obtained freeze-drying powder FP-1-2 carries out further sterilizing by ultraviolet, then pack.
Embodiment 13
Will containing cyclic ether side base amphipathic nature polyalcohol P-1(0.75g) and paclitaxel (0.2g) be dissolved in oxolane (5mL), after 0.22 micron pore membrane filtration sterilization, in an aseptic environment, the glucosan concentration joined with agitating device is 0.1%(quality) aqueous humour (50mL), stir after 3-6 hour, after solvent volatilization is clean, obtained aqueous polymer dispersion is dispensed in lyophilizing container, after freezing at-40 DEG C, lyophilization, sealed packaging; After obtained freeze-drying powder FP-1-3 carries out further sterilizing by ultraviolet, then pack.
Embodiment 14
Will containing cyclic ether side base amphipathic nature polyalcohol P-7(0.94g) and paclitaxel (0.01g) be dissolved in oxolane (5mL), after 0.22 micron pore membrane filtration sterilization, in an aseptic environment, the lactose concn joined with agitating device is 0.1%(quality) aqueous humour (50mL), stir after 3-6 hour, after solvent volatilization is clean, obtained aqueous polymer dispersion is dispensed in lyophilizing container, after freezing at-40 DEG C, lyophilization, sealed packaging; After obtained freeze-drying powder FP-2 carries out further sterilizing by ultraviolet, then pack.
Embodiment 15-22
Device and operation, with embodiment 11 ~ embodiment 14, just feed intake by the raw material composition shown in table 1, prepare other amphipathic nature polyalcohol lyophilized powder in table 2.
Table 2 is containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder composition
abe dispersed into 25% aqueous dispersions in 20 DEG C of normal saline and need the time;
bthe gelation time of 25% aqueous dispersions at 37 DEG C;
c4 DEG C store 24 months, and outward appearance, dispersibility and gelation time do not change substantially
Embodiment 23-32
First form according to table 4, preparation aqueous humour, then joins in lyophilized powder at 4 ~ 25 DEG C, is mixed by lyophilized powder, through gentle agitation or vortex 1 ~ 120min, form homogeneous flowable fluid composition with aqueous humour, forms as table 3.
Table 3 is containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder compositions
The aqueous humour that table 4 preparation table 3 lyophilized powder compositions is used
Embodiment 39
The other administration anti-tumor experiment of tumor: the balb/c mice of inoculation EAC tumor is divided into 7 groups at random, and often organize 10, gross tumor volume is greatly about 100-150mm
3between.First group is injecting normal saline; Second group of injection Blank gel; 3rd group of intravenous injection formulation for paclitaxel
dosage is 24mg/kg, point 3 injections, every injection in 5 days once; The normal saline solution (2mg/mL, 200 μ L) of the 4th group of intravenous injection doxorubicin hydrochloride, dosage is 35mg/kg, point 4 injections, every injection in 4 days once; The 5th group of other disposable injectable composition A-4(dose of paclitaxel 24mg/kg of tumor); The 6th group of other disposable injectable composition A-5(amycin 35mg/kg of tumor); 7th group of tumor other disposable injectable composition A-6(dose of paclitaxel 24mg/kg, amycin 35mg/kg).The point in time measurement gross tumor volume size of setting, the weight of animals change and animal.
Weigh Mouse Weight at regular intervals, with short diameter and the long diameter of vernier caliper measurement tumor, be calculated as follows gross tumor volume:
in formula, a is short diameter, and b is long diameter.
Antitumous effect is as table 5-7, compare with the intravenous injection of doxorubicin injection with paclitaxel injection, after the other administration of gel preparation tumor, can the growth of remarkable Tumor suppression, and Mouse Weight and survival rate are all higher, illustrate that gel topical can reduce the toxic and side effects of medicine.
Gross tumor volume meansigma methods (the cm of table 5 embodiment 33 animal
3)
| Experimental group | 1 day | 5 days | 8 days | 11 days | 14 days | 16 days | 20 days | 24 days | 30 days |
| 1 | 0.12 | 0.35 | 0.62 | 2.32 | 3.82 | 5.12 | 8.52 | 13.64 | 20.11 |
| 2 | 0.12 | 0.26 | 0.55 | 2.15 | 3.55 | 5.05 | 8.45 | 14.05 | 20.23 |
| 3 | 0.15 | 0.25 | 0.40 | 1.40 | 2.30 | 3.80 | 6.80 | 10.80 | 16.82 |
| 4 | 0.12 | 0.20 | 0.25 | 1.05 | 1.65 | 2.15 | 4.35 | 6.85 | -- |
| 5 | 0.14 | 0.24 | 0.26 | 0.56 | 1.06 | 1.46 | 1.76 | 2.06 | 2.23 |
| 6 | 0.13 | 0.18 | 0.20 | 0.40 | 0.61 | 0.73 | 0.87 | 1.15 | 1.35 |
| 7 | 0.15 | 0.16 | 0.18 | 0.28 | 0.30 | 0.32 | 0.34 | 0.33 | 0.35 |
The Weight averages (g) of table 6 embodiment 33 animal
| Experimental group | 1 day | 5 days | 8 days | 11 days | 14 days | 16 days | 20 days | 24 days | 30 days |
| 1 | 24.6 | 25.3 | 26.6 | 27.5 | 28.6 | 30.1 | 32.2 | 33.5 | 35.0 |
| 2 | 23.4 | 24.0 | 25.6 | 26.4 | 28.1 | 29.0 | 30.2 | 31.6 | 33.2 |
| 3 | 23.1 | 22.7 | 22.5 | 21.4 | 20.8 | 19.1 | 20.3 | 20.8 | 21.2 |
| 4 | 25.1 | 23.2 | 20.5 | 18.4 | 16.8 | 16.1 | 17.3 | 18.0 | -- |
| 5 | 24.4 | 25.2 | 26.6 | 28.2 | 29.6 | 31.0 | 33.2 | 34.6 | 35.2 |
| 6 | 24.1 | 25.1 | 26.5 | 27.4 | 29.6 | 30.8 | 32.2 | 33.7 | 34.5 |
| 7 | 23.0 | 24.1 | 26.3 | 28.1 | 30.1 | 31.3 | 33.2 | 34.6 | 35.2 |
The viable count (only) of table 7 embodiment 33 animal
| Experimental group | 1 day | 5 days | 8 days | 11 days | 14 days | 16 days | 20 days | 24 days | 30 days |
| 1 | 10 | 10 | 10 | 8 | 7 | 7 | 6 | 6 | 6 |
| 2 | 10 | 10 | 9 | 9 | 8 | 8 | 7 | 6 | 6 |
| 3 | 10 | 10 | 8 | 8 | 7 | 7 | 6 | 3 | 2 |
| 4 | 10 | 10 | 7 | 6 | 6 | 5 | 4 | 2 | 0 |
| 5 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| 6 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 9 | 9 |
| 7 | 10 | 10 | 10 | 10 | 10 | 10 | 9 | 9 | 9 |
Embodiment 40
Administration zoopery in the liver of compositions A-8:
Adopt human liver cancer cell bel7402, set up Orthotopic implantation in nude mice tumor model, be divided into 5 groups at random, often organize 10.First group of injecting normal saline; Injection Blank gel (the normal saline compositions of EP-12) in second group of liver; 3rd group of lumbar injection anthracene shellfish element, dosage is 0.5mg/kg; 4th group of lumbar injection anthracene shellfish element, dosage is 50mg/kg; Injectable composition A-8 in 5th group of liver, dosage is 0.5mg/kg.Tumor is taken out in different time operation, measures tumor weight, as table 8.Visible, under 0.5mg/kg dosage, in compositions A-8 liver, the antitumous effect of topical is significantly better than the anthracene shellfish element lumbar injection group of same dose, and antitumous effect and high dose lumbar injection anthracene shellfish element group (50mg/kg) are quite.Further by the mensuration of healthy mice body weight change, as Fig. 5, prove that compositions A-8 topical obviously reduces anthracene shellfish element toxic and side effects.
The meansigma methods (g) of the tumor weight of table 8 embodiment 34 animal
| Experimental group | 3 days | 9 days | 14 days |
| 1 | 2.2 | 3.5 | 4.6 |
| 2 | 2.1 | 3.2 | 4.5 |
| 3 | 1.9 | 2.65 | 4.4 |
| 4 | 1.2 | 1.2 | 0.9 |
| 5 | 1.1 | 1.2 | 0.9 |
Claims (10)
1., containing a lyophilized powder for cyclic ether side base amphipathic nature polyalcohol, it is characterized in that lyophilized powder is a kind of lyophilized powder containing amphipathic nature polyalcohol, wherein amphipathic nature polyalcohol mass content accounts for more than 65%, and freeze-dried excipient accounts for 0-10%, and medicine accounts for 0 ~ 30%; The feature of described lyophilized powder is: 20 DEG C, dispersible in normal saline within 120min formed amphipathic nature polyalcohol mass content 10% ~ 40% uniform aqueous dispersions, viscosity is less than 600Pa.s, place 6h viscosity B coefficent at 20 DEG C lower than 20%, the aqueous dispersions formed can gelation in 10min at 37 DEG C; Described amphipathic nature polyalcohol is by containing 1,4, one or more in ABA, BAB type amphipathic nature block polymer that the degradable polyester A of 8-trioxa spiral shell [4.6]-9-hendecanone (TOSUO) unit and Polyethylene Glycol B block form, wherein, polyester A is the copolymer of caprolactone, lactide, Acetic acid, hydroxy-, bimol. cyclic ester and TOSUO; TOSUO construction unit accounts for the 5-20% of A, and further preferably 7 ~ 15%; The average molecular mass of A is 1000 to 10000, and the average molecular mass of Polyethylene Glycol block is 500 to 5000; The total mass ratio of A and B is 2-4; Heavy metal <0.01% in polymer, solvent and level of residual monomers <0.5%; Described freeze-dried excipient is selected from mannitol, glucose, lactose, dextran, sucrose, gelatin hydrolysate, sodium chloride, citric acid, glycine, Glycine sodium, sodium deoxycholate, sodium dihydrogen phosphate and sodium hydrogen phosphate, sorbitol, dextran and their combination.
2. one according to claim 1 is containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder, it is characterized in that described lyophilized powder is the lyophilized powder of the amphipathic nature polyalcohol being loaded with medicine, wherein amphipathic nature polyalcohol content is more than 65%, freeze-dried excipient 0-10%, heavy metal <0.01%, water content <1%, solvent and level of residual monomers <0.5%, medicine is one or more in chemical medicine, Chinese medicine and biological species medicine, and content is 0.5 ~ 30%; Described amphipathic nature polyalcohol is by containing 1,4, one or more in ABA, BAB type amphipathic nature block polymer that the degradable polyester A of 8-trioxa spiral shell [4.6]-9-hendecanone (TOSUO) unit and Polyethylene Glycol B block form, wherein, polyester A is the copolymer of caprolactone, lactide, Acetic acid, hydroxy-, bimol. cyclic ester and TOSUO, TOSUO construction unit accounts for the 5-20% of A, and the average molecular mass of A is 1000 to 10000, and the average molecular mass of Polyethylene Glycol block is 500 to 5000; The total mass ratio of A and B is 2-4; Described freeze-dried excipient is selected from mannitol, glucose, lactose, dextran, sucrose, gelatin hydrolysate, sodium chloride, citric acid, glycine, Glycine sodium, sodium deoxycholate, sodium dihydrogen phosphate and sodium hydrogen phosphate, sorbitol, dextran and their combination; Described lyophilized powder dispersibles in normal saline and forms 25% aqueous dispersions within 20oC, 120min, and viscosity is less than 600Pa.s, and place 6h viscosity B coefficent at 20 DEG C lower than 20%, the aqueous dispersions formed is 10min inner gel at 37 DEG C.
3. a kind of lyophilized powder containing cyclic ether side base amphipathic nature polyalcohol according to claim 2, is characterized in that the medicine in described lyophilized powder is antitumor drug, comprises one or more in antitumor chemical medicine, Chinese medicine and biological species medicine.
4. a kind of lyophilized powder containing cyclic ether side base amphipathic nature polyalcohol according to claim 3, feature is the medicine in described lyophilized powder is hydrophobic anticancer drug, and lyophilized powder drug content is 1 ~ 15%, preferred paclitaxel, amycin, hydroxy camptothecin.
5. the preparation method containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder described in a claim 1-4, it is characterized in that: (1) is containing the preparation of cyclic ether side base amphipathic nature polyalcohol and purification: take Polyethylene Glycol as initiator, stannous octoate is catalyst, 1,4,8-trioxa spiral shell [4.6]-9-hendecanone and caprolactone or lactide or Acetic acid, hydroxy-, bimol. cyclic ester or their mixture are that monomer carries out ring-opening polymerisation, specifically: Polyethylene Glycol is added reactor, heating makes Polyethylene Glycol melting, natural cooling after evacuation dewaters, add caprolactone or lactide or Acetic acid, hydroxy-, bimol. cyclic ester or their mixture, TOSUO and stannous octoate successively, often add evacuation, inflated with nitrogen after a kind of reactant, last vacuum seal, reacts 3-24h under stirring at 120-160 DEG C, in reactor, add the polymer synthesized by dichloromethane dissolving, then pour in cold normal hexane and precipitate, collected by filtration thing, secondary precipitation in rear cold normal hexane is again dissolved with dichloromethane, sucking filtration isolates precipitate, vacuum drying, obtains containing cyclic ether side base amphipathic nature polyalcohol, (2) hydrophobic drug containing cyclic ether side base amphipathic nature polyalcohol and required load is dissolved in volatile organic solvent, be configured to the polymer solution of 10 ~ 20%, after 0.22 micron pore membrane filtration sterilization, under gnotobasis, join the sterile distilled water with agitating device, or contain in the aqueous humour of excipient and (or) water soluble drug, the volume ratio of aqueous humour and polymer solution is 10-100, stir, after solvent volatilization is clean, obtained aqueous polymer dispersion is dispensed in lyophilizing container, after less than-40 DEG C temperature are freezed, lyophilization, sealed packaging, obtained freeze-drying powder also can carry out sterilizing further by oxirane, then packs.
6. the compositions containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder described in a claim 1-4, it is characterized in that the flowable fluid composition that one or both and above lyophilized powder in described lyophilized powder form with the aqueous humour at least containing 75% water, wherein amphipathic nature polyalcohol content is 15 ~ 40%; At 25 DEG C, composition viscosity, at 10 ~ 600Pa.s, is placed 6 hours viscosity changes and is less than 20%, still keep syringeability, under 32-42 DEG C or body temperature environment, can form gel in 2-10min at being preferably 10 ~ 100Pa.s, 4-25 DEG C; Described aqueous humour refer to containing or not containing the injectable aqueous humour of therapeutic agent, therapeutic agent content lower than 25%, described therapeutic agent refer in chemotherapeutics, Chinese medicine and biological species medicine one or more; The total amount of the therapeutic agent in the medicine of load in lyophilized powder in lyophilized powder compositions and aqueous humour accounts for 0.1 ~ 25% of compositions; The preparation method of lyophilized powder compositions is: at 4 ~ 25 DEG C, mixed by lyophilized powder with aqueous humour, through gentle agitation or vortex 1 ~ 120min, forms homogeneous flowable fluid composition.
7. a kind of compositions containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder according to claim 6, it is characterized in that by containing paclitaxel or (with) lyophilized powder of amycin and the aqueous solution of water-soluble anti-tumor medicine form injectable fluid composition, for antitumor drug associating topical; Described water-soluble anti-tumor medicine comprise in antineoplastic chemotherapy medicine, Chinese medicine and biological species medicine one or more.
8. the compositions containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder described in claim 6 and 7, is characterized in that the adhesive agent containing 0.5 ~ 5% in described aqueous humour; Described adhesive agent is selected from hyaluronic acid, Chitosan-phospholipid complex, cyclodextrin, mucopolysaccharide, water-soluble cellulose derivative, acrylic polymer; The acid of preferably clear matter, carbomer, carbopol; Further preferred molecular weight is at the hyaluronic acid of 5-30 ten thousand.
9. the application of compositions containing cyclic ether side base amphipathic nature polyalcohol lyophilized powder described in claim 6-8, it is characterized in that as gel preparation in tumor, by tumor, thoracic cavity, abdominal cavity, intravesical, in liver, nasal cavity, ophthalmic or intravaginal topical.
10. the application of a kind of lyophilized powder compositions to be adjuvant containing the amphipathic nature polyalcohol of cyclic ether side base described in claim 9, it is characterized in that the topical for thoracic cavity, abdominal cavity, intravesical antitumor drug, method first discharges thoracic cavity, seroperitoneum or intravesical urine, then by prepare in advance fluid composition injection or be applied to medicine-feeding part.
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